PROJECT SUMMARY Psychosis is an often debilitating syndrome occurring in 40-60% of people with Alzheimer's disease (AD). Psychosis in AD (AD+P) is associated with a more severe disease course, mortality, hospitalization, carer burden and faster decline in cognition and function. Atypical antipsychotics ? first developed for schizophrenia - are widely used off license to treat these symptoms, with minimal benefits and considerable harm, including a 1.5- to 1.8-fold increase in mortality and a 3- fold increase in stroke. The development of safe and effective therapies for AD+P is an urgent priority, which has to start with a better understanding of disease mechanisms. There is abundant evidence from post-mortem, neuroimaging and genetic studies that AD-P is associated with a distinct profile of neurobiological changes but little is known about the molecular processes driving etiology. Moreover, one of the most robust clinical correlates of AD+P is a more rapid cognitive decline the trajectory of which appears to diverge before the onset of symptoms, suggests that stratification of individuals early in the disease by biomarkers that suggest the individual will develop psychosis could bring clinical benefits by identifying individuals at risk of AD+P and targeting interventions to them before the onset of symptoms. Thus, in this project we will test our overall hypothesis that AD+P is characterized by specific molecular changes in both the brain and blood that cut across multiple layers of genomic regulation. The main aim of this project is to identify novel disease mechanisms and biomarkers of AD+P, via the following specific aims; 1: Identify novel disease mechanisms implicated in AD+P; 2: Identify specific signatures of psychotic symptoms in blood samples of individuals with AD+P and evaluate their potential to predict whether individuals with MCI are more likely to develop AD; 3: Elucidate the extent to which psychotic symptoms in AD are mechanistically linked to schizophrenia The study brings together unique sample cohorts, cutting-edge methodologies and world-leading experts in genome regulation, clinical neuropsychiatry and AD neuropathology. This project builds on the state-of-the-art research methods utilized in our previously successful NIH R01 grants. The project will provide a major step forward in identifying 1) novel drug targets for AD+P, 2) better treatment of AD+P with existing medications and 3) novel peripheral biomarkers to predict which individuals with MCI will develop AD+P and are thus more likely to have a rapidly progressive disease course.